The present invention relates to a preparation containing lipase inhibitors and soluble fibers compressed into a rapidly disintegrating tablet which meets USP disintegration standards.
Orlistat, tetrahydrolipostatin, is a hypolipaemic lipstatin derivative, presently under development by Roche under the tradename Xenical(copyright). Orlistat is a potent and selective inhibitor of pancreatic lipase. It also creates a fat phase in the intestine and removes endogenous cholesterol from bile in the intestine (Scrip, 1993, 1850, 12 and 1996, 2135, 22; Ann Rep, Roche, 1993). The lipase inhibitors act within the GI tract to inhibit the enzymes which hydrolyze dietary fat to glycerol and fatty acids. This hydrolysis is the required first step for fat digestion, and enables the absorption of lipids and fats, and their subsequent utilization for energy metabolism. Inhibition of fat digestion by lipase inhibitors such as orlistat, prevents fat absorption and hence, the availability of calories from ingested lipid.
Orlistat prevents the absorption of about one third of the fat contained in food (Ann Rep, Roche, 1995). The drug has undergone numerous placebo-controlled clinical studies, involving over 5000 obese patients. Orlistat resulted in significant weight loss and had no major adverse side-effects. During the first year of a two year study, 3-times as many patients on orlistat (with a moderately reduced calorie diet) lost 10% or more body weight as compared to patients treated with placebo and diet alone. Most patients who continued into the 2nd year of the study kept the lost weight off (Scrip, 1996, 2188, 17; Press release, Roche, May 1997). The drug is also being studied in patients with Type II diabetes (Ann Rep, Roche, 1992). The first year results of a 2 year study have shown that 228 patients receiving orlistat 3xc3x97 daily as well as following a mildly hypocaloric diet have lost 65% more weight than the placebo controlled group, with almost ⅓ having lost  greater than 10% of their bodyweight (Scrip, 1996, 2135, 22).
In diet-induced obese rats, orlistat at 27 mg/kg/day caused a marked loss of body weight (65 g) and a decrease in carcass fat (54 g), despite occurrence of mild hyperphagia (11%). Fat absorption decreased from 93-94% to 17-19%. Orlistat-treated rats showed decreases in liver (13%) and retroperitoneal (RP) pad weight and an increase in small (27%) and large (38%) intestine weight (Fed Proc. 1987, 46, 1537).
The class of lipstatin inhibitors, which includes orlistat, inhibit enzymatic cleavage of fat within the intestinal lumen and largely prevents fat absorption from the intestine. Lipstatin inhibitors may be added at 0.1-100 mg ranges as a dietary additive to feedstuffs (esp. for dogs or cats) to prevent or treat adiposity and to optimize the weight of the animal. Use of these inhibitors with water insoluble fiber may further reduce fat resorption and is the subject of U.S. Pat. No. 5,540,917. Dose of orlistat plus water insoluble fiber reduces absorption of fat from the feedstuff by 1-100 (esp. 40-70)%. U.S. Pat. No. 5,540,917 does however, require large amounts of crude fiber to fat as the desired fiber content is 2-3xc3x97 the fat content intake.
The lipase inhibitors act peripherally to inhibit fat digestion, and lack CNS side-effects. Their major side-effect is the potential to cause steatorrhea, anal oil leakage and incontinence, flatulence, and GI distress.
There exists in the art, the need to develop a product which would allow human patientsxe2x80x94to sustain a treatment regiment of the lipostatin derivatives, but reduce the potential side effects, such as anal leakage, or at least minimize them. A combination a product which would reduce these side effects would also provide for an easily administered product, which is convenient to take and transport.
The present invention relates to a readily dispersible, rapidly disintegrating tablet which meets United States Pharmacopoeia standards and includes a lipstatin inhibitor, and a water soluble, non-fermentable cellulose derivative, preferably methylcellulose. The lipase inhibitors are preferably selected from among lipstatin derivatives, such as the compound tetrahydrolipostatin (orlistat). These two components are compressed into a tablet which further contain suitable diluents, in preferred w/w ratios. Preferred diluents for use with methylcellulose are edible calcium salts, such as dicalcium phosphate, dihydrate.
The need for a safe clinically effect anti-obesity compound appears to have been found in the lipase inhibitors, of which orlistat is one of several. The mode of action of the lipase inhibitors is by to block fat absorption by inhibiting gastric and pancreatic lipase enzymes which break down fat molecules to smaller absorbable fatty acids and glycerol derivatives. When taken with a well-balanced, slightly hypocaloric diet, these inhibitors will inhibit absorption of approximately 30% of ingested fat.
The weight loss obtained with clinically effective doses of orlistat are approximately the same as those obtained with CNS-acting appetite suppressant drugs, such as fenfluramine, dexfenfluramine and sibutramine (5-10% of bodyweight in 1 year). While these drugs have potential CNS, and other, toxicities these are not an issue with the lipase inhibitors as they are not absorbed from the gastrointestinal tract. However, these inhibitors do have their own side-effect issues which are gastrointestinal tract in nature. These effects can range from mild diarrhea to faecal incontinence, as well as nausea, vomiting, flatulence, abdominal pain, liquid stools, and oily stools.
While patients may find some of these side effects tolerable, others, particularly faecal incontinence and steatorrhea, are not.
The present invention, therefore provides for a swallowable solid dosage form of a combination product which contains a bulking soluble fiber, preferably methylcellulose, which is convenient to take and transport, is preferably sugar free, and a lipstatin derivative, preferably orlistat. This tablet will be easily administered to the consumer who will not need to carry and ingest a powder diluted with water along with the orlistat tablet, but preferably will have the combined tablet in one dosage form. This becomes an ideal formulation to assist in patient compliance, and to help control the undesired side effects of the lipstatin inhibitors.
Therefore, one aspect of the present invention is a pharmaceutical composition comprising:
(a) at least one water soluble, non-fermentable cellulose derivative;
(b) at least one lipase inhibitor in an amount effective for treating adiposity; and
(c) at least one excipient which is selected from an edible calcium salt; or mixtures thereof.
The lipase inhibitor is selected from: (i) a lipstatin in pure form; (ii) a biomass comprising a lipase inhibitor, the biomass being obtained by a process of fermenting a fermentation broth comprising a microorganism which produces the lipase inhibitor and separating the biomass from the fermented broth; or (iii) tetrahydrolipstatin.
Suitable lipase inhibitors, such as lipstatin and analogues thereof, tetrahydrolipstatin and N-formyl-L-leucine (S)-1-[[(2S,3S)-3-ethyl-4-oxo-2-oxetanyl]methyl]octadecylester may be used in this invention, and are described in EP 129 748, EP 185 359 and EP 444 482 respectively. Additional lipase inhibitors are esterastin and its derivatives found in U.S. Pat. Nos. 4,189,438 and 4,202,824 and biomasss or fermentation cakes obtained in the fermentative production of lipase inhibitors, such as lipstatin or esterastin are described in EP 129 748 and U.S. Pat. No. 4,189,438 whose disclosures are incorporated herein by reference in their entirety.
In an alternative embodiment of the present invention, another aspect of the present invention is a pharmaceutical composition comprising:
(a) at least one water soluble, non-fermentable cellulose derivative;
(b) at least one lipase inhibitor in an amount effective for treating adiposity; and
(c) at least one swellable diluent or filler, such as but not limited to various grades of microcrystalline cellulose, such as Avicel PH101, Avicel PH 102 and Avicel PH 200; corn starch; or Starch 1500.
Preferably the diluent in this formulation is microcrystalline cellulose. A preferred size of microcrystalline cellulose is from about 50 to 180 micron, more preferably about 50. Avicel PH 101 has a mean particle size of about 50; Avicel PH 102 has a mean particle size of about 100; and Avicel PH 200 has a mean particle size of about 190 microns. Preferably the preferred microcrystalline cellulose is Avicel PH 101.
It is noted that the ratio of methylcellulose to the swellable diluent will depend upon the diluent chosen, and is within the skill of the art to determine with preciseness the necessary ratios.
Suitable ratios for particular diluents are described below, however, to provide greater assistance (in % w/w) ratios:
For Methylcellulose: microcrystalline cellulose, from about 2:1 to about 14:1.
Preferably, for Avicel PH 101 from about 2.2-13.5:1; for Avicel PH 102 from about 2.4-8.3:1; and for Avicel PH 200 from about 2.4-4:1.
For Methylcellulose:Corn starch from about 7.5 to about 15, preferably from about 13.5:1; and
For Methylcellulose:Starch 1500, from about 2.0 to about 5.0:1, preferably from about 2.4:1.
In addition to the above noted diluents or fillers, additional components include but are not limited to, a wetting agent, a (super)disintegrant, a binding agent, dye(s) or colouring agents, and lubricants, are preferably used to prepare a tablet that is wetted readily, and is rapidly disintegrated in 0.1N hydrochloric acid and water, the USP test standard test for methylcellulose.
Preferred additional agents for these swellable diluent pharmaceutical composition are similar to those discussed below for the compositions containing the edible calcium salts.
Another aspect of the present invention is the method for dual treatment of adiposity and the faecal incontinence and steatorrhea associated therewith using a compressed tablet formulation of
(a) at least one water soluble, non-fermentable cellulose derivative;
(b) at least one lipase inhibitor in an amount effective for treating adiposity; and
(c) at least one excipient which is selected from an edible calcium salt; or mixtures thereof.
Another aspect of the present invention is the method for dual treatment of adiposity and the faecal incontinence and steatorrhea associated therewith using a compressed tablet formulation of
(a) at least one water soluble, non-fermentable cellulose derivative;
(b) at least one lipase inhibitor in an amount effective for treating adiposity; and
(c) at least one swellable diluent or filler, such as but not limited to various grades of microcrystalline cellulose, such as Avicel PH101, Avicel PH 102 and Avicel PH200; corn starch; or Starch 1500.
The dosage of orlistat in either the edible salt or swellable diluent formulation is recommended to be about 120 to 125 mg three times daily, which dosage can conveniently be formulated in a 250 to 500 mg methylcellulose tablet as described herein. However, it is recognized that in some individuals a higher dosage might be necessary, such as 50 to 250 mg three times daily, preferably 100-200 mg, more preferably 110-150 mg.
To accommodate this dosage range with the non-fermentable cellulose a tablet containing about 40 to 70, preferably about 50 to 60 mg of orlistat with about 450-500 mg methylcellulose. This would hopefully provide translate to a total daily dose of orlistat of 150 to 750 mg/day, preferably 300-600 mg/day, and more preferably about a dose of 330 to 450 mg/day range on mg/Kg basis (assuming a 75 Kg person) is 4.4 mg/kg-day to 6 mg/Kg-day, under the most optimal conditions.
A preferred non-fermentable cellulose for use herein is methylcellulose having a viscosity of  greater than 1000 centipoise. Lower molecular weight (mw) methylcellulose is less desirable for use in a rapidly disintegrating tablet formulation.
By using the testing methods for methylcellulose under standard conditions, such as those found in the USP XXII, p. 894, Apparent Viscosity method for Methylcellulose, or as discussed in Handbook of Pharmaceutical Excipients, APhA, a preferred methylcellulose for use herein should have a viscosity of  greater than 1000 centipoises (cps), preferably  greater than 2000 centipoises, more preferably  greater than 3000 centipoises, and most preferably  greater than 4000 centipoise. Higher molecular weight methylcellulose than those described is also desirable, however, the commercially availability of this grade of methylcellulose being the limiting feature. At present the upper limit commercially available is about 6000 cps, which is encompassed within the scope of this invention. One presently available methylcellulose product for use herein is Methocel A4M, made by Dow Chemical Company, Midland, Mich. as Dow Methocel A4M, having a viscosity of about 3000 to about 5,600 cps, which is within 75 to 140% of the desired target viscosity herein.
The edible calcium salts suitable for use herein include but are not limited to, dibasic calcium phosphate dihydrate, calcium phosphate anhydrous, and tribasic calcium phosphate; or mixtures thereof. A preferred edible calcium salt is the dibasic calcium phosphate dihydrate salt, which salt also provides good compressibility.
The edible calcium salt formulation may contain additional diluents or fillers which are preferably swellable agents (such as used alone in the alternative formulation), and may include, but are not limited to, various grades of microcrystalline cellulose, such as Avicel PH101, Avicel PH102, and Avicel PH200; Corn starch, cornstarch derivatives, such as maltodextrin; or Starch 1500.
In either formulation, if microcrystalline cellulose is added, it is preferably from about 50 to 180 microns in size, more preferably about 50. Avicel PH 101 has a mean particle size of about 50; Avicel PH 102 has a mean particle size of about 100; and Avicel PH 200 has a mean particle size of about 190 microns. Preferably the preferred microcrystalline cellulose is Avicel PH 101.
It is noted that the ratio of methylcellulose to edible calcium salt, and additional diluents will depend upon the diluent chosen, and is within the skill of the art to determine with preciseness the necessary ratios.
In formulating the compressed tablet suitable ratios for particular diluents are described below (in % w/w) ratios:
Suitable ratios for particular diluents however, are described below:
For Methylcellulose:Dibasic calcium phosphate, dihydrate, from about 2 to about 4:1, preferably from about 2.6-3.1:1;
For Methylcellulose:Calcium phosphate, anhydrous from about 2 to about 4:1, preferably from about 3.1:1;
Methylcellulose:Tribasic calcium phosphate, WG(copyright) from about 2 to about 4:1, preferably from about 3.1:1.
It is recognized that with the edible calcium salt, the formulation must also have an ingredient which keeps the granules together, i.e. a binding agent. A preferred binding agent is PVP, or the alternative agents noted below.
In addition to the above noted edible calcium salt(s), optional diluents or fillers, and binding agent(s), the formulation may also include additional components such as, but are not limited to, a wetting agent, (super)disintegrant(s), a second binding agent(s), dye(s) or colouring agents, and lubricants, which are preferably used to prepare a tablet that is wetted readily, and is rapidly disintegrated in 0.1N hydrochloric acid and water, the USP test standard test for methylcellulose.
A preferred wetting agent is sodium lauryl sulfate.
A preferred lubricant is magnesium stearate.
A preferred binding agent is polyvinylpyrrolidone, or PVP, such as Povidone 29K/32. Preferably, the PVP is present in an amount of about 4 to about 6.5% w/w.
A preferred disintegrating agent is sodium starch glycolate, such as Explotab(copyright). Preferably, the sodium starch glycolate is present in an amount of about 3 to about 8% w/w.
As various excipients and diluents will be formulated together, and used in combination herein, suggested % w/w ratios for various formulations are presented below. These ratios are merely illustrative of the present invention and the skilled artisan will readily recognize how to formulate the product of this invention with the addition of edible calcium or the swellable diluent (where desired).
Sodium lauryl sulfate:Explotab:Dibasic calcium phosphate, dihydrate:Povidone 29K/32:Magnesium stearate include: 0.38-0.40:3.5-7.9:20.6-24.8:4.0-6.5:0.5-1.0
Sodium lauryl sulfate:Explotab:Tribasic calcium phosphate WG(copyright): Povidone 29K/32:Magnesium stearate include: 0.40:3.5:21.6:6.4:1.0
Sodium lauryl sulfate:Explotab:Calcium phosphate, anhydrous: Povidone 29K/32:Magnesium stearate include: 0.40:3.5:21.6:6.4:1.0
Methylcellulose:sodium lauryl sulfate (SLS), from about 60 to about 170:1. preferably from about 155:1-170:1;
Methylcellulose:Povidone, preferably PVP 29K/32, from about 8 to about 22:1, preferably from about 10.4:1-16.7:1;
Methylcellulose:Magnesium stearate from about 50 to about 150; 1, preferably from about 58-132:1:
Sodium lauryl sulfate:Explotab:Avicel PH 101(copyright): Povidone 29K/32:Magnesium stearate include: 0.35-0.46:3.05-6.17:4.38-27.13:4.38-6.66:0.76-1.14
Sodium lauryl sulfate:Explotab:Avicel PH 102(copyright): Povidone 29K/32:Magnesium stearate include: 0.35-0.46:4.9-6.17:9.21-25.53:4.38-6.66:0.76-1.14
Sodium lauryl sulfate:Avicel PH 200(copyright): Povidone 29K/32:Magnesium stearate include: 0.38-0.42:19.27-25.53:5.99-6.66:0.94-1.04
Sodium lauryl sulfate:Explotab:Corn starch: Povidone 29K/32:Magnesium stearate include: 0.36-0.38:3.66-7.07:4.35-4.68:4.35-4.68:0.88-0.95
Sodium lauryl sulfate:Explotab:Starch 1500(copyright): Povidone 29K/32:Magnesium stearate include: 0.36-0.38:3.66-7.07:24.05-25.89:4.354.68:0.88-0.95
Another advantageous property of the present invention is that some of these formulations contain calcium, such as dibasic calcium phosphate dihydrate. These formulations, for instance, will contain approximately an 80 mg/dose, anticipating formulating a 0.5 gm/tabletxc3x972 tablets/dose of methylcellulose. If desired the amount of calcium can be increased in these tablets to provide increased therapeutic value to the consumer.
As will readily be seen by the working examples, there are various combinations of intra and extragranular mixing which are possible using the ingredients herein. All are encompassed within the scope of this invention. Generally, the high viscosity methylcellulose, such as Methocel A4M, will first be granulated with a binder, such as povidone, a wetting agent, such as sodium lauryl sulfate, and a suitable colouring agent to form the intragranular mixture which is then granulated. These granular components are then admixed with additional wetting agents, and disintegrating agents and finally blended with lubricant. This final granular mixture is then blended and compressed into the tablets of the present invention.
Historically, cellulose ethers, such as methylcellulose and carboxymethylcellulose have been taught as being effective bulk laxative agents. Their mechanism of action involves increasing both the water content of, and the bulk content of the stool, as well as lubricating the stool; thereby relieving constipation.
Cellulose ethers have been administered as bulk laxatives in dosage forms comprising of tablets, suspensions, and bulk powders; the latter as sugar-free or in compositions containing high amounts of sugar.
Other bulking may also be used in combination with this invention for use in reducing loose stools and diarrhea. The same property, binding water and fluid into a gel matrix, which provides stool softening in constipation, will also work to reduce stool liquidity in diarrhea.
Cellulose ethers administered as suspensions in water may contain high concentrations of sucrose or other sugars and flavors. In such formulations, the sugar competes with the cellulose ether for available water, thereby preventing the cellulose ether from hydrating sufficiently to form a gel. Furthermore, the added calories from the high level of sugars would be disfavored for use in a weight control therapy. Finally these suspensions are viscous, semi-gelatinous, visually unappealing to patients, and have poor palatability. Similarly, bulk powders of cellulose ethers often exhibit clumping of individual particles, which thus remain undissolved as they pass through the digestive tract. This could reduce bioavailability of the added lipstatin inhibitor.
There is a common belief that tableted cellulose ethers do not readily dissolve in the digestive tract because these cellulose ethers are highly hygroscopic. The outer portion of the tablet is said to form a gel-like hydrate that prevents the tablet from breaking up and greatly retards the hydration of the inner portion of the tablet.
These semi-synthetic fibers, i.e. water soluble, non-fermentable cellulose derivatives (e.g., methylcellulose, ethylcellulose, carboxymethylcellulose, hydroxypropyl-methylcellulose) have been in the food supply for decades, and are considered safe, but the beneficial clinical effects of these fibers has not been considered in the area of laxation as a compressed tablet, due to their failure to disintegrate.
The present invention overcomes this art recognized problem and involves preparation of a novel composition for the water soluble, non-fermentable fiber, in combination with a lipase inhibitor, and process of making such.
The tablets of this invention are prepared by a novel process involving a high-shear wet granulation method, followed by fluidized bed drying, milling, mixing with the other ingredients, and compression. As noted above, preferably, all excipients employed to prepare the tablets of this invention are sugar-free.
This invention therefore, provides for a novel dosage form of the above noted semi-synthetic fibers, preferably methylcellulose, with a suitable lipstatin derivative, preferably orlistat, for convenience of administration and for its ability to have rapid disintegration.
These tablets, in contrast to other tablets of methylcellulose, which have been previously formulated as 100% w/w methylcellulose in a 0.5 gm caplet have been found not to disintegrate in 0.1N HCL solution, using a conventional dissolution apparatus even after two hours. Target tablet hardness desired is between 10 and 25, preferably 8-12 SCU; a preferred target weight of each tablet of less than 750 mg; an estimated friability of less than 2.0%, more preferably less than 1.0%, and target disintegration times below 30 minutes in water and acid (shorter disintegration times, less than 10 minutes, more preferably less than 8 minutes, in 0.1N HCl and less than 15 minutes in water, more preferably about 8 minutes, are preferred).
As will readily be seen by the working examples, there are various combinations of intra and extragranular mixing which are possible using the ingredients herein. All are encompassed within the scope of this invention. Generally, the high viscosity methylcellulose, such as Methocel A4M, will first be granulated with the lipstatin derivative; a suitable diluent, such as microcrystalline cellulose; a binding agent, such as povidone; a wetting agent, such as sodium lauryl sulfate; and optionally a suitable colouring agent to form the intragranular mixture which is granulated. These granular components are then admixed with the lubricants, additional wetting agents, disintegrating agents, and any additional agents so desired. This final granular mixture is then compressed into the tablets of the present invention.
Therefore, one aspect of this invention is a process for the manufacture of a pharmaceutical tablet, which process comprises mixing
a) granulates comprising high viscosity methylcellulose of  greater than 3000 cps; a diluent selected a diluent selected from microcrystalline cellulose, corn starch, or Starch 1500, or a mixture thereof; a lipase inhibitor, and optionally together with an intra-granular disintegrant, and/or wetting agent, and/or colouring agent; with
b) an extra-granular disintegrant, and wetting agent, and optionally an extra-granular lubricant and excipient(s); and
c) compressing into a tablet.
More preferablly, is the preparation of a tablet formulation which process comprises:
a) blending together to form an intragranular mixture high viscosity methylcellulose of  greater than 3000 cps; a diluent selected from microcrystalline cellulose, corn starch, or Starch 1500, or a mixture thereof; a lipase inhibitor; a lubricating agent; and optionally a disintegrant; and
b) adding to the mixture of step (a), a PVP aqueous solution, or alternatively spraying the mixture of step (a) with a PVP aqueous solution; and preparing granulates; and
c) blending together an extragranular mixture of a wetting agent; a lubricating agent; a diluent; and a disintegrant, or a mixture thereof; and
d) compacting the granulates of step (b) with the extragranular mixture of step (c).
Yet an alternative embodiment of this invention is the admixture of the lipase inhibitor in at step c) rather than step a).
Preferably, in this process the extragranular components includes microcrystalline cellulose, sodium lauryl sulfate, sodium starch glycolate, and magnesium stearate. Alternatively, the extragranular components are starch, sodium lauryl sulfate, sodium starch glycolate, and magnesium stearate. A prefered range of sodium starch glycolate is from about 3 to about 8% w/w.
Another aspect of this invention is a process for the manufacture of a pharmaceutical tablet, which process comprises mixing
a) granulates comprising high viscosity methylcellulose of  greater than 3000 cps; at least one edible calcium salt. or mixtures thereof; a lipase inhibitor, and optionally together with an intra-granular disintegrant, and/or wetting agent, and/or colouring agent; with
b) an extra-granular disintegrant, and wetting agent, and optionally an extra-granular lubricant and excipient(s); and
c) compressing into a tablet.
An alternative embodiment of this invention is the admixture of the lipase inhibitor in step b) rather than step a), and similarly to the preferred process below.
More specifically, the process may include, preparation of a tablet formulation which process comprises:
a) blending together to form an intragranular mixture high viscosity methylcellulose of  greater than 3000 cps; at least one edible calcium salt, or mixtures thereof; a lipase inhibitor; a lubricating agent; and optionally a disintegrant; and
b) adding to the mixture of step (a), a PVP aqueous solution, or alternatively spraying the mixture of step (a) with a PVP aqueous solution; and preparing granulates; and
c) blending together an extragranular mixture of a wetting agent; a lubricating agent; a diluent; and a disintegrant, or a mixture thereof; and
d) compacting the granulates of step (b) with the extragranular mixture of step (c).
Therefore, another aspect of the present invention is the granulates of the lipstatin derivative, the water soluble, non-fermentable cellulose derivative and suitable diluents and excipients as described herein.
Therefore, another aspect of the present invention is the granulates of the lipstatin derivative, the water soluble, non-fermentable cellulose derivative and suitable diluents and excipients as described herein.
Yet another aspect of the present invention is the method of relieving faceal incontinence or anal leakage in a mammal in need thereof, which method comprises administering to said mammal, an effective amount of a water soluble, non-fermentable cellulose derivative, preferably a high viscosity methylcellulose, compressed into a tablet with a suitable diluent as is described above. This composition optionally includes an effective amount of a lipstatin derivative, such as orlistat.